1. Synthesis of paramagnetic ligands that target the C-terminal binding site of Hsp90
- Author
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Ioannis Gelis, Vishal C. Birar, Brian S. J. Blagg, and Ang Zuo
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Ligands ,01 natural sciences ,Biochemistry ,Article ,Structure-Activity Relationship ,Paramagnetism ,Phenethylamines ,Drug Discovery ,Humans ,Glycosides ,HSP90 Heat-Shock Proteins ,Binding site ,Molecular Biology ,Binding Sites ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Investigational New Drug ,Hsp90 ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Drug development ,biology.protein ,Molecular Medicine ,C-terminal binding - Abstract
Identification of a ligand binding site represents the starting point for a structure-based drug development program. Lack of a binding site hampers the development of improved ligands that modulate the protein of interest. In this letter, we describe the development of chemical tools that will allow for elucidation of the Hsp90 C-terminal ligand binding site. Our strategy is based on the preparation of paramagnetic analogs of KU-596, an investigational new drug that is currently undergoing clinical trials for the treatment of neuropathy and interacts with the Hsp90 C-terminal domain. In particular, we report the design and synthesis of three novel paramagnetic analogs of KU-596, which will be used to obtain long range distances for NMR structural studies of Hsp90 in complex with C-terminal ligands.
- Published
- 2020
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